10/08/2012
ALAT Montevideo 2012
New Drugs for COPD Klaus F. Rabe Krankenhaus Grosshansdorf & CAU Kiel
ALAT Montevideo 2012
New Drugs for COPD Bronchitis
Bronchiolitis
Hansel TT, Lancet 2009
ALAT Montevideo 2012
New Drugs for COPD Nutrition Infections Socio-economic status
Aging Populations
4
ALAT Montevideo 2012
New Drugs for COPD: Why? Adapted from GOLD
Pauwels RA and Rabe KF, Lancet 2004;364:613-620
What do Patients with COPD die from? Reported causes of mortality in patients with COPD (%) Author Site Mannino et al Hansell et al Camilli et al Huiart et al Anthonisen et al Zielinski et al Waterhouse et al Keistinen et al Vilkman et al Celli et al
USA England Tucson Canada USA Europe Europe Europe Europe USA, Spain, Venezuela
Patients with COPD Dying
Cause: COPD (%)
Cause: Cardiovasc (%)
Cause: Malign (%)
Cause: Other Respiratory (%)
1.1 million 312,000 86 2,000 149 215 103 973 1,070 162
43 60 23 14 <15 38 49 22 30 61
26 26 42 38 25 27 22 37 37 14
8 8 9 60 7 21 21 20 12
4 26 21 4 -
Wissam M. et al., Proc Am Thorac Soc 2008;5:549-555
GOLD 2011/2012
ALAT Montevideo 2012
New Drugs for COPD
Hansel TT, Lancet 2009
Innovations for the Teatment of COPDâ&#x20AC;Ś? 1st QD LABA+ICS
1st QD LABA
QMF149 QD LABA+ICS 07/14
QVA149 QD LABA+LAMA 06/13
Indacaterol QD LABA 07/10
LAMA 06/13
QD LABA 11/13
QD Triple QD LAMA & LAMA+LABA 02/14 QD Advair LABA+ICS 04/14
Aclidinium Br 09/12
2005-2008
2009
2010
2011
2012
LAMA+LABA 06/14
2013 T+1744 & 1744 Mono LAMA+LABA 01/13
Others
Symbicort COPD LABA+ICS (AZ), 02/09
Daxas Oral PDE-IV (QD) (Nycomed) 2010 Flutiform (asthma) LABA+ICS (ABBOTT), 2010
LAMA+ICS
2015
QD Triple
Generic Advair BID LABA+ICS 2012
Novel AntiInflammatory Agents
Symbicort First Patent Expires LABA+ICS 09/2012
Spiriva Patent Expires (1/18) LABA+ICS
18 month approval assumption for all products. Competitive products could be approved within one review cycle (10 months) resulting in an eight month earlier launch. Flutiform will initially launch with asthma indication Source: Business Intelligence
2014
QD Triple
QVA 149 -Pharmacotherapy of COPD V3.0
New Drugs for COPD: Role of Exacerbations
Hansel TT, Lancet 2009
Hurst JR et al. N Engl J Med 2010;363:1128-1138
ASSOCIATION OF DISEASE SEVERITY WITH THE FREQUENCY AND SEVERITY OF EXACERBATIONS
Hurst JR et al. N Engl J Med 2010;363:1128-1138
Vogelmeier C et al. N Engl J Med 2011;364:1093-1103
MACROLIDE (AZITHROMYCIN) STUDY PROPORTION OF PARTICIPANTS FREE OF ACUTE EXACERBATIONS OF COPD
Albert RK et al. N Engl J Med 2011;365:689-698.
ALAT Montevideo 2012
New Drugs for COPD
Fabbri LM, Rabe KF. Eur Respir J 2008;31:204-212
Statin Therapy and Mortality: Peripheral Arterial Disease With Associated COPD 100
No COPD / Statins
Survival (%)
75
No COPD / no Statins
50
COPD / Statins 25
COPD / no Statins 0 0 Number at risk No COPD Mild COPD Moderate COPD Severe COPD
2
4
6
8
10
Follow-up (years) 1545 476 961 327
1223 348 667 208
1018 224 505 107
824 154 345 60
610 106 229 39
Van Gestel YRBM et al., Am J Cardiol 2008;102:192-196
433 55 145 18
Abdominal Obesity and CVD risk Atherogenic Dyslipidemia Triglycerides HDL cholesterol Cholesterol/HDL cholesterol ratio "Normal" LDL cholesterol but apo B Small, dense LDL and HDL Postprandial hyperlipidemia Insulin Resistance Insulin resistance Hyperinsulinemia Hyperglycemia Type 2 diabetes Thrombotic State PAI-1 Fibrinogen
Abdominal Obesity
Inflammatory State Leptin CRP Cytokines
Metabolic Risk Factors
Inflammation
Thin fibrous cap
Lipid Core
Coronary Atherosclerosis Unstable Plaque
Risk of Acute Coronary Syndrome
Adapted from Després JP, et al. Progress in Obesity Research: 9; 2003:29-35.
ALAT Montevideo 2012
New Drugs for COPD Overall mortality
CV mortality 80
8
current smoker ex-smoker never smoker
Mortality rate %
Odds ratio
6
heavy smoker moderate smoker ex- smoker non-smoker
70
4
2
60 50 40 30 20 10
0
0 <65
65 - 79
80 - 100
FEV1 % pred
>100
<50
50 - 70
70 - 90
90 - 110
FEV1 height adjusted
Young RP et al., Eur Respir J 2007;30:616-622
>100
Time to Onset of First Major Adverse CV Event: Effect of PDE4 Inhibition 0.04
Roflumilast 500 mcg, od, p.o. + Roflumilast 250 mcg, od p.o.
Probability of event
placebo, od, p.o. 0.03
0.02
0.01
0.00 0
30
60
90
120
150
180
210
240
270
300
330
360
390
Days post-randomisation
White WB, et al. submitted
*MACE : CV death, non-fatal MI, non-fatal stroke
Weight Decrease In Obese Patients with COPD Percent weight change from baseline to end of treatment by BMI at baseline: pivotal COPD studies pool (SAF)
Calverley PMA, Rabe KF, Goehring UM, et al. Lancet 2009;374:685â&#x20AC;&#x201C;694. (supplementary webappendix).
Roflumilast and Glucose Homeostasis in Diabetes
Wouters et al, Endocrinology 2012
Roflumilast and Glucose Homeostasis in Diabetes
Wouters et al, Endocrinology 2012
10/08/2012
Safety and tolerability of NVA237, a Once Daily Long-acting Muscarinic Antagonist, in Patients with COPD
Peak FEV1 (L)
1,8
*
*
* *
1,6
1,4
1,2 Day 1
NVA237 200 μg (n=98) Standardized AUC of FEV1 (L) (5 min–5 h post-dose)
NVA237 100 μg (n=92)
Placebo (n=91)
1,8
1,6
* *
*
*
1,4
1,2
Day 28
Peak FEV1 defined as the maximum value up to 5 hours post-dose Data are presented as least squares mean + SE; *p<0.05 vs placebo
Day 1
Day 28